This invention concerns 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives having tachykinin antagonistic activity, in particular substance P antagonistic activity, and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
Substance P is a naturally occurring neuropeptide of the tachykinin family. There are ample studies showing that substance P and other tachykinins are involved in a variety of biological actions, and therefore, play an essential role in various disorders (Regoli et al., Pharmacological Reviews 46(4), 1994, p. 551-599, xe2x80x9cReceptors and Antagonists for Substance P and Related Peptidesxe2x80x9d). The development of tachykinin antagonists has led to date to a series of peptide compounds of which might be anticipated that they are metabolically too labile to be employed as pharmaceutically active substances (Longmore J. et al., DNandP 8(1), February 1995, p. 5-23, xe2x80x9cNeurokinin Receptorsxe2x80x9d). The present invention concerns nonpeptide tachykinin antagonists, in particular nonpeptide substance-P antagonists, which in general are metabolically more stable, and hence, may be more appropriate as pharmaceutically active substances.
Several nonpeptide tachykinin antagonists are disclosed in the art. For instance, EP-0,532,456-A, published on Mar. 17, 1993 by Ciba-Geigy Corp., discloses 1-acylpiperidine compounds, in particular 2-arylalkyl-1-arylcarbonyl-4-piperidinamine derivatives, and their use as substances antagonists. EP-0,655,442-A, published on May 31, 1995 by Fujisawa Pharmaceutical Co. Ltd., discloses piperazine derivatives having tachykinin antagonistic activity.
The present compounds differ therefrom in that they invariably contain a 4-substituted-(piperazine or homopiperazine)-moiety in the 4-position of a piperidine- or homopiperidine group or in the 3-position of a pyrrolidine group, and by their favourable farmacological properties.
The present invention concerns compounds of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
n is 0, 1 or 2;
m is 1 or 2, provided that if m is 2, then n is 1;
p is 1 or 2;
xe2x95x90Q is xe2x95x90O or xe2x95x90NR3;
X is a covalent bond or a bivalent radical of formula xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR3xe2x80x94;
R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo substituent of formula xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94H2xe2x80x94H2xe2x80x94Oxe2x80x94;
R2 is Ar2, Ar2C1-6alkyl, Het1 or Het1C1-6alkyl;
R3 is hydrogen or C1-6alkyl;
L is hydrogen; Ar3; C1-6alkyl; C1-6alkyl substituted with 1 or 2 substituents selected from hydroxy, C1-6alkyloxy, Ar3, Ar3C1-6alkyloxy and Het2; C3-6alkenyl; Ar3C3-6alkenyl; di(Ar3)C3-6alkenyl or a radical of formula 
xe2x80x83wherein each q independently is 2, 3 or 4;
each r is 1, 1, 2, 3 or 4;
each Y1 independently is a covalent bond, xe2x80x94Oxe2x80x94 or NR3;
Y2 is a covalent bond, C1-4alkanediyl or xe2x80x94C1-4alkylNR3xe2x80x94;
each xe2x80x94Axe2x95x90Bxe2x80x94 independently is a bivalent radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90Nxe2x80x94;
each R4 independently is hydrogen, C1-6alkyl, Ar2 or Ar2C1-6alkyl;
R5 is hydrogen, C1-6alkyl or Ar3;
R6 is C1-6alkyl, Ar3, Ar3C1-6alkyl, di(Ar3)C1-6alkyl, Ar3C3-7cycloalkyl, or indolyl;
R7 is Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; C1-6alkyl; C3-7cycloalkyl; C3-7cycloalkyl substituted with Ar3; oxazolyl; oxazolyl substituted with halo or C1-6alkyl; thiazolyl; thiazolyl substituted with halo or C1-6alkyl; imidazolyl; imidazolyl substituted with Ar3, C1-6alkyl, Ar3C1-6alkyl or halo; indolinyl; indolinyl substituted with C1-4alkyl; 2,3,4-trihydroquinolinyl; pyrrolidinyl or furanyl;
each R8 independently is hydrogen, C1-6alkyl, C3-7cycloalkyl or a radical of formula
xe2x80x94Alkxe2x80x94R11xe2x80x83xe2x80x83(b-1) or
xe2x80x94Alkxe2x80x94Zxe2x80x94R12xe2x80x83xe2x80x83(b-2);
xe2x80x83wherein Alk is C1-6alkanediyl;
Z is a bivalent radical of formula xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR3xe2x80x94;
R11 is phenyl; phenyl substituted with 1 or 2 substituents selected from halo, C1-6alkyl or C1-6alkyloxy; furanyl; furanyl substituted with 1 or 2 substituents selected from C1-6alkyl or hydroxyC1-6alkyl; thienyl; thienyl substituted with 1 or 2 substituents selected from halo or C1-6alkyl; oxazolyl; oxazolyl substituted with 1 or 2 C1-6alkyl substituents; thiazolyl; thiazolyl substituted with 1 or 2 C1-6alkyl substituents; pyridinyl or pyridinyl substituted with 1 or 2 C1-6alkyl substituents;
R12 is C1-6alkyl or C1-6alkyl substituted with hydroxy, carboxyl or C1-6alkyloxycarbonyl;
Ar1 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C1-4alkyl, haloC1-4alkyl, cyano, aminocarbonyl, C1-4alkyloxy or haloC1-4alkyloxy;
Ar2 is naphtalenyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halo, cyano, nitro, amino, mono- or di(C1-4alkyl)amino, C1-4alkyl, haloC1-4alkyl, C1-4alkyloxy, haloC1-4alkyloxy, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl and mono- or di(C1-4alkyl)aminocarbonyl;
Ar3 is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, amino, nitro, aminocarbonyl, C1-6alkyl, haloC1-6alkyl or C1-6alkyl-oxy;
Het1 is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, C1-4alkyl or mono-, di- or tri(halo)methyl; and
Het2 is a heterocycle selected from 1,4-dihydro-5-oxo-tetrazol-1-yl, imidazo[1,2-a]-pyridinyl, oxazolyl or imidazolyl; each of said heterocycles may be substituted with 1 or where possible 2 substituents selected from C1-4alkyl and Ar3.
The heterocycles in the definition of Het1 are preferably connected to the rest of the molecule, i.e. X, xe2x80x94C(xe2x95x90Q)xe2x80x94 or C1-6alkyl, by a carbon atom.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C2-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as, for example, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C1-4alkyl is meant to include C2-4alkyl and methyl; C1-5alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 carbon atoms such as, for example, pentyl, 2-methylbutyl and the like; C1-6alkyl is meant to include C1-5alkyl and the higher homologues thereof having 6 carbon atoms such as, for example, hexyl, 2-methylpentyl and the like; C1-4alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, and the like; C1-6alkanediyl is meant to include C1-4alkanediyl and the higher homologues thereof having form 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like; C3-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; and the carbon of said C3-6alkenyl connected to the nitrogen atom of the piperazine or homopiperazine preferably is saturated.
As used in the foregoing definitions and hereinafter, haloC1-4alkyl is defined as mono- or polyhalosubstituted C1-4alkyl, in particular C1-4alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, famaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
For isolation and purification purposes, it is also possible to use pharmaceutically unacceptable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically and those salts are therefore preferred.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible isomeric as well as conformational forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, more in particular the racemic mixture, of all possible stereochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configuration;  greater than Cxe2x95x90NR3 and C3-6alkenyl radicals may have the E- or Z-configuration. The compounds of formula (I) have at least two stereogenic centers; thus for compounds of which the actual stereochemical configuration is known, the relative stereodescriptors R* and S* may be used in accordance with the Chemical Abstracts rules (Chemical Substance Name Selection Manual (CA), 1982 Edition, Vol. III, Chapter 20). In those cases where the compounds of formula (I) were separated into its racemic cis and racemic trans isomers, or in those cases where the racemic cis or racemic trans isomers were separated into its pure enantiomeric forms, the stereochemically isomeric form which was first isolated was designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or mixtures thereof are intended to be embraced within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, compounds of formula (I) wherein L is a radical of formula (a-1) wherein R5 is hydrogen, or a radical of (a-2) or (a-3) wherein Y1 is xe2x80x94NHxe2x80x94, or a radical of formula (a-5) wherein R3 is hydrogen may exist in their corresponding tautomeric form. Also compounds of formula (I) wherein X is xe2x80x94NHxe2x80x94 and xe2x95x90Q is xe2x95x90O may exist in their corresponding tautomeric form.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more of the piperazine-nitrogens are N-oxidized.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms.
A special group of compounds are those compounds of formula (I) wherein L is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy; C3-6alkenyl; Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; Ar3C3-6alkenyl; di(Ar3)C1-6alkenyl; or a radical of formula (a-1), (a-2), (a-4) or (a-5) wherein
R7 is Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; C1-6alkyl; C3-7cycloalkyl; C3-7cycloalkyl substituted with Ar3; oxazolyl; oxazolyl substituted with halo or C1-6alkyl; thiazolyl; thiazolyl substituted with halo or C1-6alkyl; imidazolyl; imidazolyl substituted with Ar3, C1-6alkyl, Ar3C1-6alkyl or halo; pyrrolidinyl or furanyl;
Ar3 is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, amino, aminocarbonyl, C1-6alkyl, haloC1-6alkyl or C1-6alkyloxy;
Het1 is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom by 1 or 2 substituents selected from halo, C1-4alkyl or mono-, di- or tri(halo)methyl.
A first group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
a) R1 is Ar1C1-6alkyl; or
b) R2 is Ar2, Ar2C1-6alkyl or Het1; in particular, phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, cyano, nitro, amino, C1-4alkyl, haloC1-4alkyl, C1-4alkyloxy and C1-4alkyloxycarbonyl, more in particular, phenyl substituted with 2 substituents selected from methyl and trifluoromethyl; or
c) n is 0 or 1, in particular n is 1; or
d) m is 1; or
e) p is 1 or 2, in particular p is 1; or
f) xe2x95x90Q is xe2x95x90O; or
g) X is a covalent bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR3xe2x80x94, in particular a covalent bond.
A second group of interesting compounds consists of those compounds of formula (I) wherein L is hydrogen, Ar3; Ar3C1-6alkyl; di(Ar3)C1-6alkyl; Ar3C3-6alkenyl; C1-6alkyl substituted with hydroxy; or
a radical of formula (a-2) wherein
R4 is hydrogen or Ar2;
r is 0 or 1;
Y1 is a covalent bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR3xe2x80x94; and
R7 is Ar3, C3-7cycloalkyl substituted with Ar3, di(Ar3)methyl, pyrrolidinyl or furanyl; or
a radical of formula (a-4) wherein
Y2 a covalent bond or methylene;
xe2x80x94Axe2x95x90Bxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Nxe2x95x90CHxe2x80x94; and
R8 hydrogen, a radical of formula (b-1) wherein R11 is methyl substituted oxazolyl, or a radical of formula (b-2) wherein Z is xe2x80x94Oxe2x80x94 and R12 is C1-6alkyl; or
a radical of formula (a-5) wherein
R4 is hydrogen;
q 2; and
R3 is hydrogen.
A third group of interesting compounds consists of those compounds of formula (I) wherein
q is 2 or 4;
xe2x80x94Axe2x95x90Bxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Nxe2x95x90CHxe2x80x94;
R4 is hydrogen or Ar2;
R5 is hydrogen;
R6 is C1-6alkyl or Ar3;
R7 is Ar3; di(Ar3)C1-6alkyl; C1-6alkyl; C3-7cycloalkyl substituted with Ar3; thiazolyl; imidazolyl substituted with C1-6alkyl or Ar3C1-6alkyl; indolinyl; indolinyl substituted with C1-4alkyl; 2,3,4-trihydroquinolinyl; pyrrolidinyl or furanyl;
Z is xe2x80x94Oxe2x80x94;
R11 is phenyl substituted with halo; oxazolyl substituted with C1-6alkyl; or
R12 is C1-6alkyl.
Of special interest are those compounds of formula (I) wherein R1 is Ar1C1-6alkyl, R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl, X is a covalent bond and xe2x95x90Q is xe2x95x90O.
Further of special interest are those compounds of formula (I) wherein n and m are 1 and p is 1 or 2.
Particular compounds are those compounds of formula (I) wherein
R1 is phenylmethyl;
R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl;
n, m and p are 1;
X is a covalent bond; and
xe2x95x90Q is xe2x95x90O.
Also particular compounds are those compounds of formula (I) wherein L is a radical of formula (a-2) wherein
R4 is hydrogen or phenyl;
r is 0 or 1;
Y1 is a covalent bond, xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
R7 is pyrrolidinyl; furanyl; 1-phenylcyclohexanyl; diphenylmethyl; or phenyl substituted with 1, 2 or 3 substituents each independently selected from methyl, methoxy or chloro.
Preferred compounds are those particular compounds that have a trans configuration.
Other preferred compounds are those particular compounds that have a cis configuration.
Still other preferred compounds are those compounds of formula (I) wherein
R1 is phenylmethyl;
R2 is phenyl substituted with 2 substituents selected from methyl or trifluoromethyl;
n, m and p are 1;
X is a covalent bond;
xe2x95x90Q is xe2x95x90O;
L is a radical of formula (a-2) wherein
R4 is hydrogen;
r is 1;
Y1 is xe2x80x94NHxe2x80x94; and
R7 is phenyl substituted with 2 methyl substituents.
Most preferred are those compounds selected from
4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide;
4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(1-phenyl-cyclohexyl)-1-piperazine acetamide;
1-[3,5 -bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-[(xcex1-(1-pyrrolidinylcarbonyl)-benzyl]-1-piperazinyl]piperidine;
1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]- 1-piperazinyl]-2-(phenylmethyl)piperidine;
4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-trifluoromethylphenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide;
4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide; the N-oxides, the stereoisomeric forms
and the pharmaceutically acceptable addition salts thereof.
Particularly interesting stereoisomeric forms are
(+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide; and
(xe2x88x92)-(B)-cis-4-[1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide, and the pharmaceutically acceptable addition salts thereof, especially the (L)-malic acid form.
The compounds of formula (I) can be prepared by reductively N-alkylating an inter-mediate of formula (III) with an intermediate of formula (II). Said reductive N-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of an appropriate reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. In case a borohydride is used as a reducing agent, it may be convenient to use a complex-forming agent such as, for example, titanium(IV)isopropylate as described in J. Org. Chem, 1990, 55, 2552-2554. Using said complex-forming agent may also result in an improved cis/trans ratio in favour of the trans isomer. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. Stirring and optionally elevated temperatures and/or pressure may enhance the rate of the reaction. 
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
The compounds of formula (I) can also be prepared by reacting an intermediate of formula (IV) wherein W1 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy, with an intermediate of formula (V). The reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried at a temperature ranging between room temperature and reflux temperature. 
The compounds of formula (I) may also be converted into each other following art-known transformations. In particular, the compounds of formula (I) wherein L is other than hydrogen, said L being represented by Lxe2x80x2 and said compounds being represented by formula (I-a), can also be prepared by reacting a compound of formula (I) wherein L is hydrogen, said compounds being represented by formula (I-b), with an intermediate of formula (VI) wherein W2 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy, at reaction conditions which are similar to those for the reaction between intermediates of formula (IV) and (V). 
Compounds of formula (I-b) may be prepared by reductively N-alkylating a piperazine derivative of formula (VII) wherein P1 is a protective group such as, for example, benzyl, with an intermediate of formula (II). Said reaction may be performed in a similar way as described hereinabove for the reductive N-alkylation using intermediates (II) and (III). The thus formed compound of formula (I-c) may then be deprotected using art-known deprotection techniques. Depending on the nature of the protective group P1, compounds of formula (I-c) may be part of the scope of the compounds of formula (I). 
Alternatively, compounds of formula (I-b) may be prepared by first reductively N-alkylating a piperazine derivative of formula (VII) wherein P1 is a protective group such as, for example, halo, with an intermediate of formula (VIII) using the same procedure as described hereinabove for the reductive N-alkylation using intermediates (II) and (III). The thus formed intermediate of formula (XI) may then be reacted with an intermediate of formula (IV) in a reaction-inert solvent and optionally in the presence of a suitable base such as, for example, triethylamine, to form a compound of formula (I-c), which may then be deprotected using art-known deprotection techniques. 
The compounds of formula (I-b) are deemed to be of particular use in the synthesis of other compounds of formula (I).
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art. For example, intermediates of formula (III), (IV) and (VI) may be prepared according to art-known procedures.
Intermediates of formula (II) may be prepared by condensing an intermediate of formula (IV) with an intermediate of formula (VIII) analogous to the procedure described in EP-0,532,456-A. 
The preparation of intermediates of formula (VIII) is also described in EP-0,532,456-A. However, intermediates of formula (VIII) wherein R1 is optionally substituted Ar1C1-6alkyl or di(Ar1)C1-6alkyl, said R1 being represented by xe2x80x94CH(R1a)2 and said intermediates being represented by formula (VIII-a), may also be prepared as depicted in scheme 1. 
In scheme 1, the intermediates of formula (IX-b) may be prepared by reacting an intermediate of formula (IX-a) with an aldehyde or a ketone of formula (X). The C1-6alkylcarbamate moiety in the intermediates of formula (IX-b) may be converted into a fused oxazolone which in turn may be reduced to an intermediate of formula (IX-d). Said intermediate (IX-d) may in turn be deprotected, thus forming an intermediate of formula (VIII-a). Subsequently, intermediates of formula (VIII-a) may be reacted with an intermediate of formula (IV) to prepare intermediates of formula (II) wherein R1 is defined as xe2x80x94CH(R1a)2, said intermediates being represented by formula (II-a).
Said intermediates of formula (II-a) may also be prepared by first reacting intermediate (IX-d) with intermediate (IV) in the presence of a suitable base to form an intermediate of formula (XII), which may subsequently be deprotected. These reactions and those performed in scheme 1 may all be conducted following conventional methods that are generally known in the art. 
Intermediates of formula (V) may suitably be prepared by reacting an intermediate of formula (VIII-1), being a protected intermediate of formula (VIII) with a protecting group P2 such as, for example, a C1-6alkyloxycarbonyl group, with an intermediate of formula (III) according to the previously described reductive N-alkylation procedure, and subsequently deprotecting the thus formed intermediate. 
In particular, intermediates of formula (V) wherein R1 is xe2x80x94CH(Ra)2, said intermediates being represented by formula (V-a), may be prepared as is depicted in scheme 2. 
The ketalized intermediate of formula (IX-c) may be transformed to the corresponding ketone of formula (IX-e) which subsequently may be reductively aminated with a piperazine- or homopiperazine derivative of formula (III). The thus obtained intermediate may then be reduced with a suitable reducing agent to an intermediate of formula (V-a).
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I) have valuable pharmacological properties in that they interact with tachykinin receptors and they antagonize tachykinin-induced effects, especially substance P-induced effects, both in vivo and in vitro and are thus of use in the treatment of tachykinin-mediated diseases, and in particular in substance P-mediated diseases.
Tachykinins, also referred to as neurokinins, are a family of peptides among which substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and neuropeptide K (NPK) may be identified. They are naturally occurring in mammals, including human beings, and are distributed throughout the central and peripheral nervous system, where they act as neurotransmitters or neuromodulators. Their actions are mediated through several subtypes of receptors, such as, for example, NK1, NK2 and NK3 receptors. Substance P displays highest affinity for NK1 receptors, whereas NKA preferentially binds to NK2 receptors and NKB preferentially binds to NK3 receptors. However, the selectivity of these tachykinins is relatively poor and under physiological conditions the action of any of these tachykinins might be mediated by activation of more than one receptor type.
Substance P and other neurokinins are involved in a variety of biological actions such as pain transmission (nociception), neurogenic inflammation, smooth muscle contraction, plasma protein extravasation, vasodilation, secretion, mast cell degranulation, and also in activation of the immune system. A number of diseases are deemed to be engendered by activation of neurokinin receptors, in particular the NK1 receptor, by excessive release of substance P and other neurokinins in particular cells such as cells in the neuronal plexi of the gastrointestinal tract, unmyelinated primary sensory afferent neurons, sympathetic and parasympathetic neurons and nonneuronal cell types (DNandP 8(1), February 1995, p. 5-23, xe2x80x9cNeurokinin Receptorsxe2x80x9d by Longmore J. et al.; Pharmacological Reviews 46(4), 1994, p. 551-599, xe2x80x9cReceptors and Antagonists for Substance P and Related Peptidesxe2x80x9d by Regoli et al.).
The compounds of the present invention are potent inhibitors of neurokinin-mediated effects, in particular those mediated via the NK1 receptor, and may therefore be described as tachykinin antagonists, especially as substance P antagonists, as indicated in vitro by the antagonism of substance P-induced relaxation of pig coronary arteries which is described hereinafter. The binding affinity of the present compounds for the human, guinea-pig and gerbil neurokinin receptors may be determined in vitro in a receptor binding test using 3H-substance-P as radioligand. The subject compounds also show substance-P antagonistic activity in vivo as may be evidenced by, for instance, the antagonism of substance P-induced plasma extravasation in guinea-pigs, or the antagonism of drug-induced emesis in ferrets (Watson et al., Br. J. Pharmacol. 115, 84-94, 1995).
In view of their capability to antagonize the actions of tachykinins by blocking the tachykinin receptors, and in particular antagonizing the actions of substance P by blocking the NK1 receptor, the subject compounds are useful in the prophylactic and therapeutic treatment of tachykinin-mediated diseases such as, for example,
pain, in particular traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temperomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain; sport""s injury pain; dysmennorrhoea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain e.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosing spondyolitis; gout; bums; scar pain; itch; and thalamic pain such as post stroke thalamic pain;
respiratory and inflammatory diseases, in particular inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; inflammatory diseases of the gastrointestinal tract such as Crohn""s disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation;
emesis, i.e. nausea, retching and vomiting, including acute emesis, delayed emesis and anticipatory emesis, no matter how emesis is induced, for example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Mxc3xa9nixc3xa8re""s disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia;
central nervous system disorders, in particular psychoses such as schizophrenia, mania, dementia or other cognitive disorders e.g. Alzheimer""s disease; anxiety; AIDS-related dementia; diabetic neuropathy; multiple sclerosis; depression; Parkinson""s disease; and dependence on drugs or substances of abuse;
allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis;
gastrointestinal disorders, such as irritable bowel syndrome;
skin disorders, such as psoriasis, pruritis and sunburn;
vasospastic diseases, such as angina, vascular headache and Reynaud""s disease;
cerebral ischaemia, such as cerebral vasospasm following subarachnoid haemorrhage;
stroke, epilepsie, head trauma, spinal cord trauma and ischemic neuronal damage;
fibrosing and collagen diseases, such as scleroderma and eosinophilic fascioliasis;
disorders related to immune enhancement or suppression, such as systemic lupus erythematosus;
rheumatic diseases, such as fibrositis;
neoplastic disorders;
cell proliferation; and
cough.
The compounds of the present invention have a favourable metabolic stability and exhibit good oral availability. They also have an advantageous onset and duration of action. The compounds of formula (I) also have the ability to penetrate the central nervous system as may be demonstrated in vivo by their inhibitory effect on the change in behaviour induced by intracerebroventricular-applied substance P in the gerbil.
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from tachykinin-mediated diseases as mentioned hereinabove, in particular, pain, emesis or asthma. Said method comprises the systemic administration of an effective tachykinin antagonizing amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans. Hence, the use of a compound of formula (I) as a medicine is provided, and in particular a medicine to treat pain, emesis or asthma.
For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Acid or base addition salts of compounds of formula (I) due to their increased water solubility over the corresponding base or acid form, are obviously more suitable in the preparation of aqueous compositions.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclo-dextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-xcex2-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Those of skill in the treatment of tachykinin mediated diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.001 mg/kg to about 40 mg/kg body weight, more preferably from about 0.01 mg/kg to about 5 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose once daily or as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg to 500 mg, and in particular, 0.5 mg to 50 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.